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Initial testing of the hypoxia-activated prodrug PR-104 by the pediatric preclinical testing program by Peter J. Houghton; Richard Lock; Hernan Carol; Christopher L. Morton; Doris Phelps; Richard Gorlick; E. Anders Kolb; Stephen T. Keir; C. Patrick Reynolds; Min H. Kang; John M. Maris; Amy W. Wozniak; Yongchuan Gu; William R. Wilson; Malcolm A. Smith is a Medicine article available to read on EtoBox.

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## Abstract ## Background PR‐104 is rapidly hydrolyzed to PR‐104A in vivo, which is activated by reduction to the corresponding 5‐hydroxylamine (PR‐104H) and amine (PR‐104M) to produce DNA interstrand cross‐links. PR‐104 activation can occur via hypoxia‐dependent reductases and also independently of hypoxia by aldo‐keto reductase (AKR) 1C3. ## Procedures PR‐104A was tested against the PPTP in vitro panel (10 nM to 100 μM), and PR‐104 in vivo using a weekly × 6 schedule at its maximum tolerated dose (MTD) of 550 mg/kg. Subsequently PR‐104 was tested at 270 and 110 mg/kg. Pharmacokinetics for PR‐104 and its metabolites were determined, as were levels of AKR1C3 RNA and protein in xenografts. ## Results In vitro, the leukemia models were most sensitive to PR‐104A. In vivo, PR‐104 induced objective responses at its MTD in 21/34 solid tumor models and maintained complete responses against 7/7 acute lymphoblastic leukemia (ALL) models. At 270 mg/kg and lower dose levels, PR‐104 did not induce solid tumor regressions, suggesting a steep dose–response relationship. Pharmacokinetic analysis suggests higher systemic exposures to PR‐104A and its metabolites in mice compared to those achievable

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Author

Peter J. Houghton; Richard Lock; Hernan Carol; Christopher L. Morton; Doris Phelps; Richard Gorlick; E. Anders Kolb; Stephen T. Keir; C. Patrick Reynolds; Min H. Kang; John M. Maris; Amy W. Wozniak; Yongchuan Gu; William R. Wilson; Malcolm A. Smith

Publisher

John Wiley and Sons; Wiley (John Wiley & Sons); John Wiley & Sons Inc.; Wiley (ISSN 1545-5009)

Published

2010

Language

EN

Field

Medicine (Health Sciences)